5, 10-methylene-19-nor- and 5, 10-seco-5, 19-cyclo-10-fluoro-androstenes and pregnenes and processes for their preparation



United States Patent 24 Claims. (Cl. 260-3976) This invention relates to novel cyclopentanoperhydrophenanthrene derivatives and to processes for their preparation.

More particularly, this invention relates to novel 5,10- rnethylene-19-nor-steroids and 5,10 seco 5,19-cyclo-10- fluoro steroids of the androstane and pregnane series and to processes for their preparation, said steroids being represented by the general formulas:

wherein R represents hydrogen or an acyl group containing less than 12 carbon atoms; R represents hydrogen, a lower alkyl group, such as methyl, ethyl, propyl and the like, a lower alkenyl group, e.g., vinyl, or a lower alkinyl group, e.g., ethinyl; R and R each represent hydrogen, hydroxyl or an acyloxy radical containing less than 12 carbon atoms, R represents hydrogen, a-rnethyl, B-methyl or a-hydroxylg R and R taken together can also represent the grouping:

wherein R represents hydrogen or a lower alkyl group, e.g., methyl, ethyl, propyl and the like, and R represents hydrogen or a lower alkyl, aryl, e.g., phenyl, aralkyl, e.g., tolyl, or alkaryl, e.g., benzyl group; X represents hydrogen, fluorine or chlorine and Y represents hydrogen, fl-hydroxyl or keto, with X being hydrogen when Y is hydrogen and both X and Y being hydrogen when R is hydrogen.

The acyloxy and acyl groups referred to above are derived from hydrocarbon carboXylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, or aromatic, and may be substituted by functional groups such as hydroXy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, amino acetate, and fi-chloropropionate.

The novel 5,10-methy1ene-19-nor-pregnenes and 5,10- seco 5,19 cyclo 10 fluoro pregnenes represented by Formulas III and IV above can also be represented by the following more specific formulas:

0H CH OR |....,R, M X Q k/J v11 L/V vnr In these formulas R R, X and Y have the same meaning as set forth hereinabove for Formulas III and IV, and R represents hydrogen or an acyl group containing less than 12 carbon atoms.

The compounds represented by Formulas I and II are anabolic agents having a favorable anabolic-androgenic ratio. They also possess anti-estrogenic activity, inhibit the pituitary gland, and favor the deposition of calcium in bones.

The compounds represented by Formulas V and VII are progestational agents with anti-estrogenic activity. In addition, they inhibit ovulation and also show certain diuretic activity. Thus, they are useful in the maintenance of pregnancy and in fertility control. They also relieve premenstrual tension.

The compounds represented by Formulas VI and VIII are corticoid hormones having anti-inflammatory activity, useful in the treatment of arthritis, rheumatism, allergic dermatitis and eye and ear infiarnrnations.

In accordance with the present invention the surprising discovery has been made that when a A -3-keto19-hydroxy steroid is treated with 1 to 2 molar equivalents of an a-fluorinated amine of the type ACF N (A wherein A represents a fiuorinated lower alkyl group, such as difluoromethyl, chloro-fluoromethyl and the like, and A represents a lower alkyl group, such as methyl, ethyl, propyl and the like, in an inert organic solvent containing no acidic hydrogen, at reflux temperature for a period of time in the order of about 30 minutes to about 1 hour, or at about 0 to 20 C. for a prolonged period of time, pref er-a'bly between about 16 and about 24 hours, there are produced mixtures of 5,l0 seco-5,19 cyclo-10fl-fiuoroA 3-keto and 5,lO-cyclo-19-nor-A -3-keto compounds, in accordance with the following equation, wherein only rings A and B of the steroid molecule are represented:

35 (CHFClcF NEt and 1,1,2,Z-tetrafluoroethyldimethylamine. These reagents are preparedin accordance with the method described by N. N. Yarovenko et al. in Journal of General Chemistry of the U.S.S.R., 29, 1259 (1959).

Suitable solvents for use in this reaction include acetonitrile, methylene chloride; ethers such as diethyl ether, isopropyl ether, dioxane, tetrahydrofuran, Dowanol, etc; aromatic hydrocarbons such as benzene, toluene, xylene, etc. In general, the reaction may be carried out in any organic solvent containing no acidic hydrogen.

When the above-described reaction is conducted under milder conditions, i.e., at room temperature for about 30 minutes to about 1 hour or at about 50 C. to about 90 C. for about 5 to minutes, there are obtained the 5,10- seco 5,19 cyclo 10,8 fluoro compounds and a small amount of the IOa-fluoro isomers.

Essentially any 19-hydroxy-A -3-keto steroid containing from 19 to 21 carbon atoms in the steroid nucleus may be used in carrying out the process of the present invention and a variety of substituents may be present in different positions of the steroid molecule, without efiecting the course of the reaction. Thus, for example, keto groups may be present at the 11-, 17- and/or -positions, methyl groups may be present at (3-6 or C-16, and alkyl, alkenyl or alkinyl radicals may be present in the 1706- position (androstane derivatives). In the case of com- ,acid solution, then with'water, 10% sodium carbonate pounds having hydroxyl groups, such as for example at the 11-, 17- and/or 21-positions, it is recommended that the hydroxyl groups be protected, preferably by selective esterification or by formation of the 17,20;20,21-bismethylenedioxy derivative in the case of compounds possessing the dehydroacetone side chain.

Several reactions may also be effected after the reaction with the fiuorinated' amine. Thus, for example, a hydroxyl group may be introduced at the ll-position by microbiological methods, and the resulting ll-hydroxylated compounds may also be oxidized to the correspond-' ing ll-keto derivatives or transformed into the 9a-haloll-oxygenated compounds by following the method described by Fried et al. in J. Am. Chem. Soc. 75, 2273 (1953). V

A hydroxyl group may 'be introduced at C-16 by incubation with Streptomyces roseochromogenus.

The 21-hydroxyl groups may be eliminated by known methods, such as for example, by formation of the 21- tosylate and elimination of the tosyloxy group by reflux with sodium iodide in acetic acid.

The cfollowing examples serve to illustrate but are not intended to limit the scope of the present invention:

PREPARATION I A solution of 5 g. of M-androstene-Sfi,19-diol-17-one (US. Patent 3,065,228) in 250 cc. of thiophene-free benzene was treated with 27.5 cc. of a 4 N-ether solution of methyl magnesium bromide and the mixture was refluxed for 3 hours in the absence of moisture. The cooled mixture was cautiously treated with an excess of aqueous solution of ammonium chloride and the product was isolated by extraction with ethyl acetate.

The extract was washed with Water, dried over anhydrous sodium sulfate and evaporated to dryness.

By recrystallization from methylene chloride-hexane there was obtained 17a-methyl-A -androstenedfl,17,13,19- triol.

A -andr0stene-35,19-diol-17-one was treated in accordance with the above procedure, except that methyl magnesium bromide was substituted by ethinyl magnesium bromide and by vinyl magnesium bromide, giving respectively 17m ethinyl A androstene 35,175,19 trioland 17a-vinyl-A -androstene-3fl,17,8,19-triol.

PREPARATION II V Asolution .ofl g. of 17a-methyI-A -androstene-3B,17B,

19-triol in 10 cc. of toluene and 2 cc. of cyclohexanone solution and water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. By crystal lization from acetonehexane there was obtained 17ozmethyl-A androstene-17p, 19-diol-3 -one.

PREPARATION III A mixture of 1 g. of 17a-ethinyl-A -androstene-3B,17B,- 19-triol, 1 g. of p-toluenesulfonic acid, 50. cc. of acetic acid and 25 cc. of acetic anhydride was kept at room temperature for 24 hours. Then it was poured into water and stirred until the excess anhydride was hydrolyzed. The product was isolated by addition of methylene chloride, and by crystallization of the residue from acetone-ether, there was obtained the tri-acetate of 170cethinyl-A -androstene-3 3,1713,19-trio1.

To a solution of 1 g. of the latter tri-acetate in 100 cc; of methanol, was added 1 gram of potassium carbonate dissolved in 10 cc. of water. The resulting mixture was kept for 2 hours at room temperature, then it was neutralized with approximately 1 cc. of acetic acid and concentrated to a small volume. Water was added and the product extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. By crystallization from acetonehexane there was obtained the 17-acetate of 1704- ethinyl-M-androstenefi,17,8,19-triol.

PREPARATION IV The compounds listed under I (described in US. Patent 3,065,228) were treated in accordance with Preparation 11, thus giving the respective products set forth under II.

I II

20-one. 1G S-methyI-A -pregnen-3B,19-diol- 20-one.

16a,17a-isopropylidenedioxy-N- pregnene-iifl,19-di0l-20-0ne.

17-acetate of A -pregnen-3fl,17a19- tr1ol-20-one.

17-acetate of 16a-methyl-A pregnen-3B,17a,19-trio1-20-one.

17-acetate of 17a-ethinyl-A androstene-319,176,19-tri01.

-tr10l. 17zg-yiftyl-A -androstene'3 3,17,9,19-

no 17 ,20 ;20,2l-bismethylenedicxy-A pregnene-3B,19-diol-ll-0ne. 17,20;20,21-bismethylenedioxy-A drone. 16a,17a-isopropylidenedioxy-A pregnen-19-ol-3,20-dione. 17-acetate of A -pregnen-17a,19-

diol3,20-dione. 17-acetate of lfia-methyl-N- pregnene-l7a,19-dio1-l3-,20-dione.

l7-acetate of 17zx-ethinyl-A androstene-176,19-di0l-3-0ne. 17a-ethiny1-A -androstene-173,19-

dio1-3-0ne. 17avinyl-A -androstene-1713,19-

diol-3-one. 17,20;20,21-bismethylenedioxy-A pregnen-19-ol-3,11-dione. 17,20;20,21bismethylenedi0xy-A pregnene-3B,l9-di01. pregnen-l9-ol-3-one.

Example I 270-272 my, 10 E 3.80

Further elutionwith the same mixture of solvents gave .15 g. of 5,10-seco-5,19-cyclo-ZOB-fluoro-M-androstene- ,17-dione; M.P. 179-180 (3.; [0. 68 cHcn rage 240-242 my, log 6 4.09 Example [I was added dropvvise in a 15 minutes period to a stirred suspension of 3 g. of lithium aluminum hydride in 150 cc. of anhydrous tetrahydrofuran. The mixture was heated at reflux temperature for 12 hours, cooled and treated carefully with 10 cc. of ethyl acetate and 5 cc.

ol-3,20-dione.

16fl-methyl-A -pregnen-19 ol-3,20-dione 164:,17a-isopropylidcnedioxy- A -preg'nen-19-o1-330- dioue.

17 acetate of A -pregnene 17a,l9-dlO1*3,20-di0118.

17 acetate of lfia-methyl-N- pregnene-l7a,19-di0l-3,20- dione.

17,20;20,21-bismethylenedixyA -pregnenl9-01-3,11- dione.

17,20;20,21-bismethylencdioxy-N-pregnen-l9-ol-3-one.

l9-nor-A -preguene-3,20- dione. 5,l0-rnethy1ene16flmethyl- 19-nor-A -pregneue-3,20 dione. 5,10methylene-16 17wisopropylidenedioxy-lQ-nor- A'-pregueue-3,20-dione.

5,10methylene-19-nor-A pregnen-17a-ol-3,20-dione acetate.

5,10-methylene-ltia-methyl- IQ-nor-A pregneD-I 70:Ol- 3,20-dione acetate.

17,20;2D,21-bismethylenedi cry-5,10-rnethylene-19- nor-o -pregneneddl dione.

17,20;20,ZX-bismethylenedioxy-5,1U-methylene-19- nor-A pregnen-3-one.

To a solution of 7.5 g. of 19-hydroxy-A -androsteneof water. Solid sodium sulfate was then added, the m- 3,17-dione in 100 cc. of anhydrous tetrahydrofuran there Organic material filtered ofi and Washed several times was added 5.65 g. of 2-chloro-1,1,Z-trifiuorotriethylamine wit o t y c p evascration of the combined and the reaction mixture was kept at room temperature rganic solutions there Was obtained a crude product for 1 hour, it was then evaporated to dryness under rewhich Was purified by crystallization from acetone-hexduced pressure and chromatographed over 300 g. of ans, thus giving 5,10-methylene-19-nor-A -androstene-3B, Florisil to produce 5,l0-seco-5,l9-cyclo-10.8fiuoro-A 17B-diol. androstene-3,17-dione, identical to that obtained in the A solution of 2 g. of the foregoing compound in 150 previous example, and a small amount of 5,10-seco-5,19- cc. of chloroform distilled over calcium chloride was cycle-l0u-fluoro-A -androstene-3,17-dione. oxidized by stirring for 18 hours at room temperature Example In With 20 g. of freshly precipitated manganese dioxide. The

inorganic material Was filtered, Washed with hot chloro- In the mBthOd of Example 1, theft/Was used anhydrous form and the solution evaported to dryness. Crystalliza tetra'hydmfllrafl instead of acetollltrlle, tojmduce also tion of the residue from acetone gave 5,=10-rnethylene-19 5,1o-methvlene-l9-nvr-A1-andr0stene-3,17-d10ne an 9- 2O n0r-A -androsten17fi-ol-3-one; M.P. 155457 0.; MD seco, 5, l9-cyclo-10gS-fluoro-M-androstene-3,17-d1one 1n 12 -101 A max. 2 10g e similar yields. In a similar manner, 5,-1O-seco-S,19-cyclo-10fifiuoro- Example 1 A -androst-en-3,17-di0ne was converted into 5,10-seco-5,

Example I was repeated but using 1,1,2,2-tetrafluoro- 25 19 cyvlo fluoro A andmsten 17B 013 ethyldimethylamine (1.5 molar equivalents) instead of 2- Example VII chloro-l,1,2-trifiuorotriethylamine, thus producing the same products that in said example, in similar yields. BY fohflwmg the method Example the compounds 'llStBd below were converted into the corresponding 5,10- Exflmple V methylene-l9-norand 5,10 seco 5,19-cyolo-10fl-fiuoro- A solution of 5 g. of 17a-methyl-A androstene-17o,19- 3O derivatives, which were separated by chromatography on diol-S-one in 150 cc. of acetonitrile distilled over phos- Fl risil- Starting materials Products IQ-hydroxy progesterone. 5,1O-rnethylene-lQ-nor-A 5,10-seeo-5,19-cycl0-10flpreguene-bgttdione. gggg-n preguene-djo- Itia-methyI-N-pregnen-IQ- 5,10-methy1ene1fia-methyl- 5,IO-Seeo-SJQcycIQ-IUB- one.

Example VI A solution of 3 g. of 5.1O mcthylened9-nor-A -androstone-3,17-dione in 150 cc. of anhydrous tetrahydrofuran Example VIII To a solution of 1 g. of 19-hydroxy progesterone in 200 cc. of anhydrous ether there was added 1.2 molar equivalents of l,-l,2,2-tetrafiuoroethyldimethylamine, and the reaction mixture =l ept at room temperature for minutes. It was then evaporated to dryness under vacuo and the residue chromatographed on 250 g. of Florisil, thus producing 5,10-seco-5,'l9-cyclo-lOdfiuoro-Mmregnene-3,20-dione (identical to the product obtained in the preceding example} and 5,10-seco-5,1-9-cyc10-10u-iluoro- A -pregnene-iZO-dione.

Example IX A mixture of 1 g. of 17,20;20,2l-bismethylenedioxy-S, l0-scco-5,19-cyclo-10,B-fiuoro-A -pregnene-3,l-l-dione and 20 cc. of formic acid was heated on the steambath for 1 hour; it was cooled poured into Water and the formed precipitate collected by filtration. Upon crystallization from acetoneether there was obtained 5,10-secoeasaeea 7 5,19 cyclo 10fi-tluoro-A4-pregnene l7u,21-diol-3,1 l,20-' trione.

By the same method, the compounds listed below under I were hydrolyzed, thus producing the compounds under II.

I II

17,20;20,21-bismethylenedioxy- 5,10-methylene-lQ-nor-N-pregnene 3, ll-dione. 17,20-20,21-bisrnethylenedioxy- 5, 10,methylene-IQ-nOr-A -pregnen-3-one. 17,20;20,2l-bismethylenedioxy- 5, 10-seco-5, 19-cycl0-10B-fiuor0- A -pregnen-3-one.

5, 10-methylene-19-norA pregnene-17a,21-diol-3,11,20- trione.

5, lO-methylene-lSJ-nOr-A -pregheme-17a, 21-di01-3, ZO-dione.

anhydride was kept at room temperature overnight; it was poured into ice-water and the formed precipitate collected by filtration, Washed with water and dried. Upon crystallization from acetone-hexane there was obtained the acetate of 5,1O-methylene-19-noreA -androsten-17,8-ol-3-one.

By the same method, 5,10-methylene-19-nor-A -pregnene-17o,21-dio1-3,20-dione, 5,10 seco 5,19 cyclo-lOB- fiuoro-A -pregnene-17a,21-diol-3,20'dione and 5,10-methylene-19-nor-A -pregnene-11,8,17a,21-triol-3,20-dione were 10 converted into the corresponding 21-monoacetates.

Example XII By following the method described in the preceding example, the compounds listed below under I were treated 15 with the indicated acid anhydrides, to produce the respective 17 or 21 esters (II).

I Aeylating II agent 5,1O-seco-5,l9-cycl0-10B-fiuoro-A Propionic 21-propionate of 5,10sec-5,19-

pregnen-l7a,2l-di0l-3,11,ZO-trione. anhydride. cycle-1ufi-fluoro-n -pregnene- 17a,2l-di0l-3,11 ,20-trione. 5,10-scoo-5,19-cyclo-1Ofl-fluoro-A Acetic anhy- 21-acetate of 5,10-seco-5,19-eyclopregnene-11B,17a,21-tri0l-3,20- dride. 1OB-fluoro-N-pregnene-l1fi,17a,21- dione. triol-3,20-dione. 5,10-seco-5,1Q-cyelo-IOfldiuoro-A Cyelopentyl- Cyclopentylpropionate of 5,10-

androsten-17B-0L3-one. propionic seco-5,19-cyc10-10B-fluoro-A anyhdride. andr0sten-17B-01-3-one. 5,10-methylene-lQ-nor-N-nndrosten- Oaproic an- Caproate of 5,10-1uethylene-19- 17/3-ol-3-oue. hydride. nor-A -androsten-l7B-o1-3-one. -1Omethyleue-lQ-nOr-A -pregnene- Acetic anhy- 21-acetate of 5,10-methylene-19- 17a,21-d1ol-3,1l,20-trione. dride. nor-A -pregnene-l7a,21-diol- 3,11,20-trione.

Example XIII Example X By following the method described in Example VI, 2 g.

To a solution of 500 mg. of 5,10-methylene-17a-methof 17,20;20,21- bismethylenedioxy-S,10-seco-5,19-cycl0- 35 yl-19-nor A -androsten-l7B-ol-3-one in 20 cc. of an- IOB-fiuoro-M-pregnene-S,1l-dione were reduced with lithium aluminum hydride, thus producing 17,20;20,21- bismethylenedioxy-S,10-seco-5,19-cyclo B fiuoro-A pregnene-3 8,11,B-diol.

A mixture of 1 g. of the foregoing compound, cc. of dioxane and 1.1 molar equivalents of 2,3-dichl0ro-5,6- dicyano-1,4-benzoquinone was stirred at room temperature for 3 hours. The hydroquinone formed was filtered oil and the filtrate evaporated to dryness. The residue was dissolved in acetone and filtered through 20 g. 'of alumina, to produce 17,20;20,2l-bismethylenedioxy-S,10-

seco-S,19-cyc1o-IOB-fluoro-N-pregnen 11/3 ol- 3 one.

After hydrolysis of the bismethylenedioxy group with hydrous benzene there were added 100 mg. of .p-toluenesulfonic acid and 2 cc. of acetic anhydride and the mixture was allowed to stand for 24 hours at room temperature, poured into ice and water, and the resulting mixture stirred to etfect hydrolysis of the excess anhydride. The benzene layer was separated and washed with 10% sodium carbonate solution and water. Drying, evaporation and crystallization of the residue from acetonehexane produced the acetate of 5,10-methylene-l7a-methyl-19-nor-A -androsten-17,8-01-3-one.

In a similar manner, the compounds below mentioned (I) were esterified with the indicated anhydrides, to produce the corresponding esters.

% formic acid, by following the method described in Example IX, there was obtained 5,10-seco-5,19-cyclo- 10B-fluoro-A -pregnene-11fl,17a,21-triol-3 ,20-dione.

In a similar manner, starting from 17,20;20,21-bismetl1- ylenedioxy-S,10-methylene-19-nor A pregnene 3,11- dione there was produced as final product, 5,10-rnethylene-19-nor-A -pregnene-11,8,17a,21-triol-3,2O-dione.

. Example XI J A mixture of 1 g. of 5,1O-methylene-19-nor-A -androsten-17l3-ol-3-o'ne, 4 cc. of pyridine and 4 cc. of acetic To a solution of 5 g. of the acetate of 5,10-methylene 16a-methyl-19-nor-A -pregnen-17a-ol 3,20 dione acetate in 5 00 cc. of methanol there were added 500 mg. of pa tassium hydroxide dissolved in 1 cc. of water and the mix ture was refluxed for 1 hour at room temperature, poured into water and the formed precipitate collected by filtration, thus producing 5,10-methylene-16a-methyl-19-norn -pregnen-17e-ol-3,20-dione. V

A cooled solution of 4 g. of the preceding compound in 30 cc. of tetrahydrofuran and 18 cc. of methanol was' treated under continuous stirring with 6 g. of pure calcium oxide, in small portions, and then with 6 g. of iodine. The stirring was continued at room temperature until the solution turned pale yellow. The mixture was poured into ice water containing 18 cc. of acetic acid and 2 g. of sodium thiosulfate. After stirring for 15 minutes the solution was decanted and the precipitate was collected by filtration, thus giving 2l-iodo-S,IO-nrethylenela-methyl-19-nor-A -pregnen-17e-ol-3,20 dione. This compound was mixed with 80 cc. of acetone and 12 g. of recently fused potassium acetate and the mixture was refluxed for 8 hours, concentrated to a small volume, diluted with water, and extracted with ethyl acetate; the extract was washed with water, dried over anhydrous sodium sulfate and concentrated until crystallization started. The precipitate was collected and crystallized from methanol-water, thus yielding the 2l-acetate of 5,-lO-methylene-l6a-methyl-l9 nor A -pregnene-17a,=2 ldiol-3,20-dione.

A solution of 1 g. of the preceding compound in 50 cc. of methanol was treated with 3 cc. of a 5% potassium hydroxide solution, under nitrogen atmosphere, and the mixture was allowed to stand at C. for 1 hour. It was then diluted with water and the formed precipitate collected by filtration, to produce 5,'10-methylene-.16amethyl-l9-nor-A -pregnene-l7a,2l-diol-3,20-dione.

In a similar manner, starting from SAG-methylene- 16a,17a-isopropylidenedioxy-l 9 nor A -pregnene-'3,2O- dione there were obtained -5,l0-methylene-16a,l7u-isopropylidenedioxy-19-nor-A -pregnen 21 ol-3,20-dione acetate and the free compound.

Example XV Glucose 20 g.

(NH4)2HPO4 g. or NaNO 3 g. K2HPO4 lg.

MgSO .7H O 0.2 g.

KCl 0.5 g.

ZnSO Traces.

FeSO .7H O Traces.

Distilled Water to complete 1 It.

The cultures were incubated under rotatory stirring for 72 hours at 25 C. The growth was homogenized for 1 minute in a Waring Blender; 2 cc. portions of the suspension thus obtained were employed for inoculating approximately 100 Erlenmeyer flasks containing the same medium described above. The mixtures were incubated for 24 hours under rotatory stirring at 25 C. and 280 r.p.m.; to each flask there was added 0.5 cc. of a solution of 0.5 g. of 5, -methylene-16ot-methyl-19- nor-.d -pregnene l7ot,21 diol 3,20 dione, in 50 cc. of 95% ethanol and the incubation was continued under the same conditions for 48 hours. The contents of the flasks were combined and extracted with four portions of methylene chloride. The combined extract was dried over anhydrous sodium sulfate and concentrated at low temperature to a volume of 25 cc. This solution was absorbed on 4 g. of silica gel and eluted with methylene chloride (9:1) to produce 5,IO-methylene-16a-methyl- 1 9-nor-A -pregnene-1 1f),17a,2l-triol-3, ZO-dione.

By the same method 5,10-methylene-16a,17rx-isopropylidenedioxy-'l-9 nor A -pregnen-21-ol-3,20-dione was converted into 5,10 methylene 160;,170: isopropylidenedioxy-19-nor-A -pregnene-11 p,21-diol-'3,20-dione.

10 Example X V] In accordance with the method described in Example XI, the compounds obtained in the preceding example were converted into the corresponding acetates.

Example XVII A solution of 1.1 equivalents of chromic acid in 5 cc. of acetic acid was added dropwise to a stirred solution of 1 g. of the 21-acetate of 5,10-methylene-19- nor-A pregnene-l1;3,l7a,21-triol-3,20-dione in 40 cc. of glacial acetic acid maintaining the temperature around 20 C. After 2 hours at room temperature the mixture was poured into ice water and the formed precipitate filtered, washed with water and recrystallized from methanol, thus giving the 21-acetate of 5,10-methylene- 19-nor-A -pregnene-17 2 l -diol-3 ,1 1,20-trione.

In a similar manner, the 2l-acetate of 5,10-methylene- 1601.,17a isopropylidenedioxy-19-nor-A pregnene-:l'1,8,21- diol-3,20-dione, the 21-acetate of 5,10-methylene-l6amethyl-l9-nor-A -pregnene-115,l7a,21-triol 3,20 dione were converted respectively into the 2l-acetate of 5,10- rnethylene 16,17u isopropylidenedioxy 19 nor-A pregnen-2l-ol-3,11,20-trione, the 21-acetate of 5,10- methylene-l6a-methyl-l9-nor-A -pregnene l7ot,21 diol- 3 ,1 1,20-trione.

Example X VIII A cold solution of 5 g. of the ZI-acetate of 5,10- methylene-l9-nor-A -pregnene-l 1fi,17a,21-triol-3,ZO-dione in 5 cc. of dimethylforrn-amide was treated with 2.8 g. of mesyl chloride and 2.5 cc. of pyridine and the solution was kept at 80 C. for half an hour. The reaction mixture was cooled, water was added and the product was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. Recrystallization of the residue from acetone-hexane furnished the 21-acetate of 5,10 rnethylene-19-nor-A -pregnadienel70;,21-di0l- 3,20-dione.

To a stirred solution of 2 g. of the latter compound in 20 cc. of pure dioxane there were added 0.4 cc. of 3 N- perchloric acid and 1 g. of N-bromoacetamide during 30 minutes.

The reaction mixture was stirred for 1 hour further, a solution of 10% sodium sulfite was then added until the potassium-starch indicator paper no longer turned blue, ice was added, the mixture was extracted with chloroform and the extract was washed consecutively with water, 5% aqueous sodium bicarbonate solution and water, and the solvent was removed by distillation under vacuo. By trituration of the residue with acetone there was obtained the corresponding bromohydrin.

A mixture of 2 g. of anhydrous potassium acetate and 20 cc. of acetone was heated almost to boiling and then a solution of 1.7 g. of the bromohydrin, in 20 cc. of acetone was added slowly while stirring; the mixture was then refluxed for 10 hours, cooled and almost all of the acetone was distilled off; iced-water was then added, the precipitate was filtered, washed with water and dried. Upon recrystallization from methylene chloride-benzene there was obtained the 21-acetate of 5,10-methylene-95, 1 lfi-oxido-l9-nor-A -pregnene-17a,21-diol-3,20-dione.

In a polyethylene flask, adapted with a magnetic stirrer, there was dissolved 0.9 g. of the foregoing compound in 15 cc. of methylene chloride, the solution was cooled to 0 C. and a solution of 1.1 g. of anhydrous hydrogen fluoride in 3.7 cc. of tetrahydrofuran cooled in a Dry Ice acetone bath (70 C.) was added over a period of 20 minutes with constant stirring. The mixture was stirred at a temperature lower than 10 C. for 6 additional hours, then neutralized by cautiously adding a 5% aqueous sodium bicarbonate solution and transferred to a separatory funnel. The organic layer was washed with water,

1 1 dried over anhydrous sodium sulfate and concentrated until formation of an abundant precipitate. The mixture was cooled, the precipitate filtered and redissolved in hot ethyl acetate, the insoluble material was filtered OE and the filtrate cooled whereby the 21-acetate of 5,10-methylene-9oe-fiuor0-19-nor-A -p1'egnene 11,8,17a,21 triol-3,20- dione crystallized.

By the same method, the 21-acetate of 5,10-methylene- 16ix-methyl-19-nor-A -pregnene 11fi,17uc,21 triol3,20- dione, the 21-acetate of 5,10-methylene-16a,17m-isopropylidenedioXy-19 nor-A -pregnene 11,5,21 did-3,20- dione and the 2l-acetate of S,10-seco-5,19-cyclo-10B- fluoro-A -pregnene-llfi,17a,21-triol-3,20-dione were converted into the corresponding 9m-fiuoro-derivatives.

To a solution of 1 g. of the 21-acetate of 5,10-methylene-16a-methyl 95,11 8 oxido-19'-nor-A -pregnene-17a, 21-diol-3,20-dione, obtained in accordance with the preceding example, in 10 cc. of anhydrous chloroform, was added, over a period of 15 minutes, 8 cc. of 0.45 N solution of dry hydrogen chloride in chloroform, under continuous stirring and maintaining the temperature around C. The mixture was then stirred at 0 C. for 1 hour further, diluted with water and the chloroform layer was separated, washed with aqueous sodium bicarbonate solution and then with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. Crystallization of the residue from acetone-hexane gave the 21-acetate of 5,10 methylene-16a-methyl-9achloro 19 nor-N-pregnene-l1B,17a,21-trio1-3,20-dione.

The latter compound was oxidized with 8 N chromic acid in acetone, in accordance with the method described in Example III, to give the 21-acetate of 5,10-methylene- 16a-methyl 9a chloro-19-nor-A -pregnene-17oc,2l-diol- 3,11,20 -trione.

I claim:

1. A compound represented by the formula:

wherein R is selected from the group consisting of hydrogen and an acyl group containing less than 12 carbon atoms and R is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl and lower alkinyl.

2. 5,l0-methylene-19-nor-A -androsten-17fl-ol-3-one.

3. 5,10-methylene 17a methyl-19-nor-A -androsten- 17,8-o1-3-one.

4. A compound representing by the formula:

wherein R is selected from the group consisting of hydrogen, hydroxyl and an acyloxy group containing less than 12 carbon atoms; R is selected from the group consisting of hydrogen, a-methyl, fi-methyl and u-hydroxy, and R and R taken together represent the grouping 6. The acetate of 5,IO-methylene-19-nor-A -pregnen- 17a-ol-3,20-dione.

7. A compound represented by the formula:

CHgOR wherein R is hydroxyl; R is selected from the group consisting of hydrogen, a-methyl, li-methyl and a-hydroxyl; R and R taken together represent the grouping wherein R is selected from the group consisting of hydrogen and lower alkyl and R is selected from the group consisting of hydrogen, lower alkyl, monocyclic aryl, monocyclic aralkyl and monocyclic alka-ryl; R is selected from the group consisting of hydrogen and an acyl group containing less than 12 carbon atoms; X is selected from the group consisting of hydrogen, fluorine and chlorine and Y is selected from the group consisting of hydrogen, fi-hydroxyl and keto, with X being hydrogen when Y is hydrogen. 7

8. 5,1O-methylene-l9-nor-A -pregnene-17a,21-diol-3,20- dione.

9. 5,IO-methylene-19-nor-A -pregnene-1 1fi,17a,21-triol- 3,20-dione.

10. 5,10-methylene 19 nor-A -pregnene-17u,2l-diol- 3,11,20-trione.

1 1. A compound represented. by the formula:

wherein R is selected from the group consisting of hydrogen, hydroxyl and an acyloxy group containing less than 12 carbon atoms; R is selected from the group consisting 13 of hydrogen, ct-methyl, B-rnethyl and cx-hYdlOXY, and R and R taken together represent the grouping wherein R is selected from the group consisting of hydrogen and lower alkyl and R is selected from the group consisting of hydrogen, lower alkyl, monocyclic aryl, monocyclic aral-kyl and monocyclic alkaryl.

14. 5,10 seco-5,19-cyclo-105-fluoro-A -pregnene-3,20- dione.

15. A compound represented by the formula:

CHZOR7 1 Y -3 wherein R is hydroxyl; R is selected from the group consisting of hydrogen, cx-methyl, fi-methyl and oz-hydroxyl; R and R taken together represent the grouping 14 containing less than 12 carbon atoms; X is selected from the group consisting of hydrogen, fluorine and chlorine and Y is selected from the group consisting of hydrogen, fi-hydroxyl and keto, with X being hydrogen when Y is hydrogen.

16. 5,10-seco-5, 19-cyclo-10/3-fiuoro-A -pregnene 170:,21- diol-3,20-dione.

17. 5,10 seco-S,19-cyclo-lOfi-fiuoro-n -pregnene-l16, 17a, 21-triol-3,20-dione.

18. 5, 1 O-seco-S, 19-cyclo-IOfl-fluoro-M-pregnene-l 7oc,2 1- diol-3, 1 1,20-t1'ione.

19. A process for the preparation of 5,10-rnethylene- 19-nor-A -3-ketoand 5,1O-seco-5,19-cyclo-l0-fiuoro-A -3- keto-steroids of the androstane and pregnane series from the corresponding 19-hydroxy-A -3-keto steroid which comprises treating said 19-hydroxy steroid, in an inert organic solvent containing no acidic hydrogen, with a fiuorinated amine represented by the general formula:

ACF N (A 2 wherein A represents a fiuorinated lower alkyl group and A represents a lower alkyl group.

20. A process as described in claim 19 wherein the fiuorinated amine is Z-chloro-l,1,Z-trifluorotriethylamine.

21. A process as described in claim 19 wherein the fluorinated amine is 1,1,2,Z-tetrafluoroethyldimethylamine.

22. A process as described in claim 19 wherein the inert organo solvent is acetonitrile.

23. A process as described in claim 19 wherein the inert organic solvent is tetrahydrofuran.

24. A process as described in claim 19 wherein the reaction is conducted at reflux temperature for about 30 to about minutes.

No references cited.

LEWIS GOTTS, Primary Examiner. 

4. A COMPOUND REPRESENTING BY THE FORMULA: 